瘢痕切除、脱细胞支架与人诱导多能干细胞来源的神经干细胞/祖细胞移植联合治疗对慢性完全性脊髓损伤的组织学影响
Histological effects of combined therapy involving scar resection, decellularized scaffolds, and human iPSC-NS/PCs transplantation in chronic complete spinal cord injury.
作者信息
Ito Keitaro, Shinozaki Munehisa, Hashimoto Shogo, Saijo Yusuke, Suematsu Yu, Tanaka Tomoharu, Nishi Kotaro, Yagi Hiroshi, Shibata Shinsuke, Kitagawa Yuko, Nakamura Masaya, Okano Hideyuki, Kohyama Jun, Nagoshi Narihito
机构信息
Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan.
Keio University Regenerative Medicine Research Center, 3-25-10 Tonomachi, Kawasaki-Ku, Kawasaki, Kanagawa, 210-0821, Japan.
出版信息
Sci Rep. 2024 Dec 28;14(1):31500. doi: 10.1038/s41598-024-82959-7.
Chronic complete spinal cord injury (SCI) is difficult to treat because of scar formation and cavitary lesions. While human iPS cell-derived neural stem/progenitor cell (hNS/PC) therapy shows promise, its efficacy is limited without the structural support needed to address cavitary lesions. Our study investigated a combined approach involving surgical scar resection, decellularized extracellular matrix (dECM) hydrogel as a scaffold, and hNS/PC transplantation. To mitigate risks such as prion disease associated with spinal cord-derived dECM, we used kidney-derived dECM hydrogel. This material was chosen for its biocompatibility and angiogenic potential. In vitro studies with dorsal root ganglia (DRG) confirmed its ability to support axonal growth. In a chronic SCI rat model, scar resection enhanced the local microenvironment by increasing neuroprotective microglia and macrophages, while reducing inhibitory factors that prevent axonal regeneration. The combination of scar resection and dECM hydrogel further promoted vascular endothelial cell migration. These changes improved the survival of transplanted hNS/PCs and facilitated host axon regeneration. Overall, the integrated approach of scar resection, dECM hydrogel scaffolding, and hNS/PC transplantation has been proven to be a more effective treatment strategy for chronic SCI. However, despite histological improvements, no functional recovery occurred and further research is needed to enhance functional outcomes.
慢性完全性脊髓损伤(SCI)因瘢痕形成和空洞性病变而难以治疗。虽然人诱导多能干细胞衍生的神经干/祖细胞(hNS/PC)疗法显示出前景,但在缺乏解决空洞性病变所需的结构支持的情况下,其疗效有限。我们的研究调查了一种联合方法,包括手术切除瘢痕、使用脱细胞细胞外基质(dECM)水凝胶作为支架以及移植hNS/PC。为了降低与脊髓源性dECM相关的朊病毒病等风险,我们使用了肾源性dECM水凝胶。选择这种材料是因其生物相容性和血管生成潜力。对背根神经节(DRG)的体外研究证实了其支持轴突生长的能力。在慢性SCI大鼠模型中,瘢痕切除通过增加具有神经保护作用的小胶质细胞和巨噬细胞来改善局部微环境,同时减少阻止轴突再生的抑制因子。瘢痕切除与dECM水凝胶的联合进一步促进了血管内皮细胞迁移。这些变化提高了移植的hNS/PC的存活率,并促进了宿主轴突再生。总体而言,瘢痕切除、dECM水凝胶支架和hNS/PC移植的综合方法已被证明是治疗慢性SCI更有效的策略。然而,尽管组织学上有所改善,但并未出现功能恢复,需要进一步研究以提高功能结果。